A primary focus of drug research is the development of analgesics for pain management. Analgesics render sensory pathways insensible or less sensible to pain, whereas anesthetics act on all sensory pathways rendering them insensible to pain, temperature, touch, proprioception and skeletal muscle tone. As such, although anesthetics can be used for pain management, their utility is limited by their inhibition of these other sensory pathways. For example, it may be desired to control a patient's pain associated with an oral mucosal lesion without interfering with senses of touch, proprioception (to avoid biting of the tongue) or taste (so as not to interfere with appetite), which is not generally possible with topical anesthetics (for example, Benzocaine) which are not able to selectively inhibit pain. The use of analgesics to control pain in such circumstances is therefore desirable.
Analgesics are generally classified as either narcotic (opioids) or non-narcotic. Narcotic analgesics primarily act on the central nervous system and carry potentially life-threatening side-effects such as addiction, impaired higher cortical function and depressed respiration. As a result, their use is regulated and they may only be prescribed by licensed practitioners. Non-narcotic analgesics include salicylates, such as aspirin; acetaminophen; and non-steroidal anti-inflammatory drugs (“NSAIDS”), such as cyclooxygenase-2 (“Cox-2”) inhibitors. Such non-narcotic analgesics can be limited in their ability to control pain and may have the side effects of chemical irritation, anticoagulation, myocardial infarction and stroke. Accordingly, there is a continuing need for the discovery and development of new analgesics, and in particular non-narcotic analgesics, that are useful for the localized management of pain without an undesirable side effects profile.
In this regard, various plant-derived compounds have been investigated for their analgesic properties. For example, capsaicin, a vanillyl alkaloid that is the source of pungency in hot peppers, has been used to treat the pain of arthritis, osteoarthritis, and various peripheral neuropathies. See, for example, Cordell and Araujo, The Annals of Pharmacotherapy, (1993) 27:330; Levinson, (January/February 1995) The Sciences, pp. 13-15. However, the therapeutic usefulness of capsaicin is limited due to an adverse side effects profile that includes burning sensations and erythema, and such side effects may persist over time. By way of further example, extracts of sweet bell peppers (Capsicum annuum) have been shown to exhibit analgesic properties (see, for example, U.S. Pat. Nos. 6,060,060 and 6,086,888), but the specific compound(s) responsible for such analgesic effects have not been identified. Furthermore, as such extracts must be derived from naturally-occurring fruit, their production and practical use is limited.
Moreover, certain naturally-occurring flavonoid glycosides have been reported, including luteolin 7-(6″-β-D-apiofuranosyl)-β-D-glucopyranoside, alternatively named: 7-[(6-O-D*-apio-beta-D*-furanosyl-beta-D*-glucopyranosyl)oxy]-2-(3,4-dihydroxyphenyl)-5-hydroxy-4H-1-benzopyran-4-one (Bucar, F. et al. Phytochemistry (1998), 48 573-575), but have not been shown to be therapeutically useful.